EP1003490B1 - Transdermales therapeutisches system (tts) zur verabreichung von sexualsteroidhormonen - Google Patents
Transdermales therapeutisches system (tts) zur verabreichung von sexualsteroidhormonen Download PDFInfo
- Publication number
- EP1003490B1 EP1003490B1 EP98939550A EP98939550A EP1003490B1 EP 1003490 B1 EP1003490 B1 EP 1003490B1 EP 98939550 A EP98939550 A EP 98939550A EP 98939550 A EP98939550 A EP 98939550A EP 1003490 B1 EP1003490 B1 EP 1003490B1
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- tts
- skin
- steroid hormone
- active substance
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- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
Definitions
- the present invention relates to a transdermal therapeutic system (TTS) for Administration of sex steroid hormones through the skin over long periods, and a method for its preparation without the use of solvents, the is particularly gentle on the active ingredient.
- TTS transdermal therapeutic system
- the bioavailability of orally administered active ingredients is often unsatisfactory.
- the Hepatic metabolism of many active substances can increase during the first passage through the liver undesirable concentration ratios, toxic by-products and Decrease in effectiveness or even lead to loss of effectiveness.
- the transdermal administration of active substances has various advantages.
- the Active ingredient supply can be better controlled over a longer period of time, which means high Fluctuations in blood levels can be avoided.
- the required therapeutic effective dose can usually be significantly reduced.
- a patch from Patients often preferred more than once or several times a day Tablets.
- Examples include: U.S.P. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,995, 4,588,580; 4,645,502; 4,702,282; 4,788,062; 4,816,258; 4,849,226; 4,908,027; 4,943,435 and 5,004,610.
- transdermal administration is only available for those few active substances Available that has a suitable combination of many favorable characteristics exhibit. For a certain active ingredient, all required characteristics are the ensure safe and effective transdermal administration, neither theoretically still practically predictable.
- TTS Transdermal Therapeutic Systems
- Polyester films made of polyester, polypropylene, Polyethylene, polyurethane etc. used, which can also be metallized or pigmented can.
- the removable protective layer i.a. Polyester films, Polypropylene or paper with silicone and / or polyethylene coating in Consideration.
- polyacrylate silicone, polyisobutylene, butyl rubber, Styrene / butadiene copolymer or styrene / isoprene copolymer used.
- the membranes used in membrane systems can be microporous or semi-permeable be and are usually based on an inert polymer, in particular Polypropylene, polyvinyl acetate or silicone are formed.
- active ingredient-containing matrix compositions can be self-adhesive, however, there are also active substance-dependent substances depending on the active substance used Matrices that are not self-adhesive, as a result of which the plaster or TTS constructively must be provided with an overtape.
- Skin penetration enhancers are often used to ensure the required flux rate of the active ingredient such as aliphatic, cycloaliphatic and / or aromatic-aliphatic Alcohols, each mono- or polyvalent and each containing up to 8 carbon atoms Alcohol / water mixture, a saturated and / or unsaturated fatty alcohol with each 8 to 18 carbon atoms, each a saturated and / or unsaturated fatty acid 8 to 18 carbon atoms and / or their esters and vitamins required as an additive.
- the active ingredient such as aliphatic, cycloaliphatic and / or aromatic-aliphatic Alcohols, each mono- or polyvalent and each containing up to 8 carbon atoms Alcohol / water mixture, a saturated and / or unsaturated fatty alcohol with each 8 to 18 carbon atoms, each a saturated and / or unsaturated fatty acid 8 to 18 carbon atoms and / or their esters and vitamins required as an additive.
- stabilizers such as polyvinylpyrrolidone, ⁇ -tocopherol succinate, Propyl gallate, methionine, cysteine and / or cysteine hydrochloride, the active ingredient Matrix added.
- transdermal systems which contain a monolithic, thermoplastic polymer film in which an active ingredient, preferably nicotine, is homogeneously distributed, and a process for the solvent-free production of this active ingredient-containing layer by mixing the active ingredient with the polymeric carrier material in the polymer melt at temperatures of 170 ° C to 200 ° C.
- An additional contact adhesive film which is applied to the active ingredient matrix and, if necessary, an additional plaster, which is applied to the active ingredient-containing polymer film on the side of the matrix facing away from the skin, is used to fix the active ingredient-containing matrix film on the skin.
- the recipes described generally require the use of organic ones Solvents that have to be removed quantitatively during production.
- the usual ones are also pharmaceutical quality requirements regarding adhesive properties, reproducibility drug release and storage stability because of the difficulties described above to guarantee only with high technical effort in the development and production.
- Large patches often have to be applied, especially for Administration of progestogens to the therapeutically required active substance levels in the Maintain blood over a multi-day period of use, which, on the one hand the performance characteristics and the associated patient compliance deteriorate, secondly, further increase the cost of the preparation.
- WO 94/26257 describes steroid-containing pressure sensitive adhesives described, which contain esters of rosin and in which the preparation an estradiol- and / or levonorgestrel-containing adhesive matrix by melting and intensive kneading at high temperature can take place over longer periods of time.
- transdermal Therapeutic systems that are manufactured in this way have the Disadvantage that the active ingredient and / or pharmaceutical additives partially decompose the conditions of the manufacturing process that the adhesive properties and / or skin tolerance of the patch is insufficient for several days, and - in particular for the progestogen component - the achievable plasma concentrations not therapeutically sufficient.
- Active ingredient plasters are also known from EP 0 186 019, in which a rubber adhesive resin composition water-swellable polymers are added and from which estradiol can be released, in individual cases also using the hotmelt process is possible. Even with these recipes it is difficult to find sufficient ones Keep levels of sex steroid hormones in solution in the patch matrix and over release through the skin for longer periods at an approximately constant rate.
- TTS has the advantage for the patient that it is not on the relatively permeable Scrotal skin must be glued, which is due to otherwise too little absorption of active ingredients Testosterone patches without penetration mediators (e.g. according to DE OS 35 23 065) the case is.
- Testosterone patches without penetration mediators e.g. according to DE OS 35 23 065
- such "enhanced" systems can be used for more than 24 hours associated with an increased risk of local skin irritation due to skin permeation of testosterone controlling additives. It can be especially bad Application conditions (sweating, heavy skin movements, showering) Problems with the adhesive properties occur.
- a TTS containing steroid hormones and a method are used to solve this problem its manufacture without the use of solvents, whose special composition surprisingly the above task enough.
- the transdermal therapeutic system (TTS) contains one steroid hormone-containing matrix mass in the form of a layer, the matrix mass at up to (200) C melt-extruded, ammonio group-containing (meth) acrylate copolymers and at least one plasticizer alone or in a mixture with an ethylene acrylate terpolymer and / or polyethylene glycol and at least 2% by weight of each in the Matrix mass unmelted steroid hormone present and to the outside with is provided with a cover layer.
- TTS transdermal therapeutic system
- the laminate of top layer and containing steroid With the exception of its release surface on the skin, matrix mass is either from surrounded by a larger active substance-free skin patch, which is used to fix the TTS to the Application site and / or to cover the active ingredient-containing matrix on the open Edges is used, or there is an active ingredient-free adhesive film on the skin side of the release surface applied.
- a larger active substance-free skin patch which is used to fix the TTS to the Application site and / or to cover the active ingredient-containing matrix on the open Edges is used, or there is an active ingredient-free adhesive film on the skin side of the release surface applied.
- the following can be used as an active ingredient-free adhesive film: covalently crosslinkable acrylate copolymers or silicone-based polymers.
- the adhesive properties of the active substance-containing matrix and the skin patch provided as a fixing aid complement one another in such a way that an immediate contact between the active substance matrix and the skin is produced immediately after the TTS has been stuck on, which contact with a relatively small area of skin patch is also possible Active substance-free adhesive edge of only about 3.5 mm wide is retained over several days (example: With a total of 20 cm 2 large, square-shaped TTS with rounded corners (including fixing aid), the area of the active substance-containing matrix can be up to approx. 15 cm 2 large his).
- the self-adhesive TTS obtained in this way consisting of top layer, active substance layer and adhesive layer, also has a surprisingly high steroid release rate over longer application periods (cf. Fig. 1, Example 2).
- Tributyl citrate is particularly advantageous as a plasticizer.
- the embodiment according to the invention in which the steroid hormone-containing is particularly advantageous Matrix mass is a solid solution.
- TTS according to the invention can be used alone or in estrogens or progestogens Combination of the same included.
- a TTS according to the invention can have androgens contain.
- the carrier film used for the TTS advantageously has a matrix side Metal vapor or oxide coating.
- TTS for fixing the active substance matrix on the skin and / or to cover the matrix on the open edges a larger active ingredient-free skin patch or an active ingredient-free adhesive film a cross-linked acrylate copolymer directly laminated to the active ingredient-containing polymer matrix
- the TTS according to the invention are provided with a protective film which is applied prior to application of the preparation is removed from the skin.
- a major advantage of the method according to the invention is that the Drug reservoir (I) is produced without the use of organic solvents, and (II) the preparation of the active substance-containing matrix mass and its further processing to a layer containing active ingredients in a continuous and particularly cost-saving Work done: Process times can be reduced to a few minutes and at the same time the risk of decomposition reactions in the polymer melt containing the active ingredient reduce to a minimum. It was surprisingly found that the complete dissolution of the sex steroid (s) in the polymer melt despite the short process times under the process conditions further explained in the examples is guaranteed.
- a twin-screw extruder equipped with three dosing units is fed continuously in successive process zones with Eudragit RS 100 (copolymer of ethyl acrylate and methyl methacrylate with approx. 5% trimethylammonioethyl methacrylate chloride), tributyl citrate (TBC) and 17 ⁇ -estradiol hemihydrate, the mixture having a total throughput of 150 g Mass / min is melt extruded at a temperature of 130-150 ° C.
- Eudragit RS 100 is fed from metering unit 1 to the process section of the extruder at a rate of 97.2 g / min, tributyl citrate from metering unit 2 at a rate of 45.82 g / min and finally from metering unit 3, 17 ⁇ -estradiol hemihydrate in a range of 6.975 g / min.
- carrier film The sheet-like three-layer laminate obtained in this way is wound on rolls and then punched out into 8 cm 2 pieces.
- the resulting TTS contain approximately 2.88 mg 17 ⁇ -estradiol, calculated as hemihydrate.
- the TTS are applied to the skin after removal of the siliconized polyester film with a 16 cm 2 active substance-free skin patch ("overtape") consisting of a pressure-sensitive adhesive film based on a crosslinked acrylate copolymer and a carrier film.
- a twin-screw extruder equipped with four metering units is continuously operated in successive process zones with Eudragit RS 100 (copolymer of ethyl acrylate and methyl methacrylate with approx. 5% trimethylammoniomethacrylate chloride), Eudragit E 100 (copolymer of butyl methacrylate, methyl methacrylate and 2-dimethylaminoethyl methacrylate with amine 25-methacrylate) ), Tributyl citrate (TBC) and 17 ⁇ -estradiol hemihydrate.
- the mixture is melt extruded at a total throughput of 150 g / min at a temperature of 130-150 ° C.
- Eudragit RS 100 (1) and Eudragit E 100 (2) are dosed using units 1 and 2 at a rate of (1) 42.75 g / min. or (2) 59.85 g / min introduced into the first process zone of the extruder.
- TBC are added by means of metering unit 3 at a rate of 39.9 g / min and estradiol hemihydrate by means of metering unit 4 at a rate of 7.5 g / min.
- the further processing is carried out in accordance with Example 1, the laminate obtained after the coating in webs having 3 layers and consisting of protective film, active substance-containing matrix with a basis weight of 80 g / m 2 and carrier film being punched into 16 cm 2 pieces.
- the resulting self-adhesive TTS contain approximately 6.4 mg 17 ⁇ -estradiol calculated as hemihydrate.
- a TTS with a punched-out area of 5 cm 2 is attached in a modified Franz diffusion cell to a skin preparation of hairless mice. Immediately afterwards, the cell is filled with distilled water as the release medium without air bubbles and thermostatted to 37 ⁇ 0.5 ° C.
- the release medium is replaced with fresh 37 ⁇ 0.5 ° C thermostatted water exchanged.
- estradiol content in the release medium taken in each case is determined by means of high-pressure liquid chromatography.
- the results of the tests are shown in Table 1 for Examples 1 and 2 as well as a comparative example and a commercially available matrix patch with a declared release of 50 ⁇ g estradiol per day. As the comparison of the flux rates shows, significantly more estradiol is released through the skin from the TTS according to the invention than in the comparison systems.
- Example 2 0.36 0.36 4.65 3.72 74.2 33.1 131.6 71.0 171.1 104.4 Comparative example (DE 43 10 012) 0.40 5.00 24.0 48.0 70.5
- Commercial preparation 0.20 2.50 22.9 38.8 51.8
- the washout phase between 2 treatments was at least 1 week.
- To the To determine transepidermally absorbed amounts of active substance was the subject in blood taken at specified intervals.
- a sensitive GC / MS method was used in the blood plasma (Limit of quantification: 5pg / ml).
- a twin-screw extruder equipped with four dosing units is continuously fed in successive process zones with Eudragit RS 100 (copolymer of ethyl acrylate and methyl methacrylate with approx. 5% trimethylammonioethyl methacrylate chloride), tributyl citrate (TBC), 17 ⁇ -estradiol hemihydrate and norethisterone acetate, with a total of the mixture being fed through the mixture 116.7 g mass / min is melt extruded at a temperature of 130-150 ° C.
- Eudragit RS 100 is fed to the process section of the extruder from dosing unit 1 at a rate of 62.24 g / min, tributyl citrate from dosing unit 2 at a rate of 29.34 g / min, and 17 ⁇ -estradiol hemihydrate from dosing station 3 of 4.667 g / min and finally from dosing station 4 norethisterone acetate at a rate of 20.417 g / min.
- the hot estradiol-norethisterone acetate-polymer melt obtained is fed via a heatable feed hose directly into a continuous stream, to the application head of the coating system and laminated to an approx.
- TTS reservoirs contain approximately 5.12 mg of 17 ⁇ -estradiol, calculated as hemihydrate and approximately 22.40 mg of norethisterone acetate.
- the TTS are covered with a 32 cm 2 active substance-free skin patch ("overtape") consisting of a pressure-sensitive adhesive film based on a crosslinked acrylate copolymer and a carrier film.
- overtape active substance-free skin patch
- E2 estradiol
- NETa norethisterone acetate
- the determination is carried out as described under II.
- the measured flux rates are in the table 4 reproduced, together with the active substance content of the test samples. Like the table can be seen, can be combination according to the inventive method TTS with a high NETa content in a high flux rate due to excised skin preparations produce.
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Description
- Hautdurchgängigkeit,
- keine Beeinträchtigung des Klebevermögens des Pflasters durch den Wirkstoff,
- Vermeidung von Hautirritationen,
- Vermeidung von allergischen Reaktionen,
- günstige pharmakokinetische Eigenschaften,
- günstige pharmakodynamische Eigenschaften,
- ein relativ weites therapeutisches Fenster,
- Metabolismuseigenschaften, die konsistent mit der therapeutischen Anwendung bei kontinuierlicher Gabe sind.
und
- a) "lösemittelfrei":
- zur Herstellung der Polymermatrices werden keine Lösungsmittel verwendet, die im Verlaufe des Herstellungsverfahrens wieder weitgehend entfernt werden, wie dieses im sogenannten "solvent based"-Verfahren geschieht,
- b) "längere Applikationszeiträume":
- die TTS können zur therapeutischen Anwendung bis zu 7 Tage auf die Haut appliziert werden.
- c) "feste Lösung":
- der pharmazeutische Wirkstoff liegt in der Pflastermatrix molekulardispers verteilt vor.
- d) "transepidermal":
- ist sinn- und funktionsgleich mit transcutan
- e) "thermisch minimiert belasteter Wirkstoff":
- der Wirkstoff wird ungeschmolzen der bei der Schmelzextrusion erhitzten Matrixmasse zugeführt, die nach Wirkstoffzusatz gegekühlt wird.
Estradiol-Fluxraten | |||||
TTS | Estradiolgehalt (Hemihydrat) mg/cm2 | Gew.-% | Kumulative Fluxrate (µg/cm2), Mittelwerte, n=3 nach | ||
24 h | 48 h | 72 h | |||
Beispiel 1 Beispiel 2 | 0,36 0,36 | 4,65 3,72 | 74,2 33,1 | 131,6 71,0 | 171,1 104,4 |
Vergleichsbeispiel (DE 43 10 012) | 0,40 | 5,00 | 24,0 | 48,0 | 70,5 |
Handelspräparat (Matrixpflaster) | 0,20 | 2,50 | 22,9 | 38,8 | 51,8 |
Fluxraten von Estradiol (E2)- und Norethisteronazetat (NETa) durch exzidierte Mäuse-haut | |||||
Beispiel 6 | Wirkstoffgehalt | Kumulative Fluxraten µg/cm2, Mittelwerte, n=3 | |||
mg/cm2 | Gew.-% | nach 24 h | nach 48 h | nach 72 h | |
E2 (Hemihydrat) | 0,3 | 4,0 | 16,0 | 33,2 | 48,9 |
NETa | 1,4 | 17,5 | 34,3 | 73,9 | 114,5 |
Claims (11)
- Transdermales Therapeutisches System (TTS) zur transcutanen Verabreichung von Sexualsteroiden über längere Zeiträume mit einer Fixierungshilfe für das TTS auf der Haut, dadurch gekennzeichnet, daß das TTS eine schichtförmige steroidhormonhaltige Matrixmasse enthält, die ammonio-gruppenhaltige (Meth)acrylatcopolymere und mindestens einen Weichmacher alleine oder in Mischung mit einem Ethylenacrylat-Terpolymeren, wenigstens 2 Gewichtsprozent von jedem in der Matrixmasse molekulardispers verteilten Steroidhormon enthält und dieses, mit Ausnahme seiner Freisetzungsfläche auf der Haut, von einem größeren wirkstofffreien Pflaster zur Fixierung an der Applikationsstelle umgeben ist.
- TTS nach Anspruch 1, dadurch gekennzeichnet, daß kantseitig auf die steroidhormonhaltige Matrixmasse ein wirkstofffreier Klebefilm, bestehend aus vernetzten Acrylatcopolymeren aufgetragen ist, der die wirkstoffhaltige Matrix auf der Haut fixiert.
- TTS nach Ansprüchen 1 oder 2, dadurch gekennzeichnet, daß es mindestens einen thermisch minimiert belasteten Wirkstoff enthält.
- TTS nach Ansprüchen 1 bis 3, dadurch gekennzeichnet, daß die steroidhormonhaltige Matrixmasse eine feste Lösung ist.
- TTS nach Ansprüchen 1 bis 4, dadurch gekennzeichnet, daß die steroidhormonhaltige Matrixmasse mindestens einen Weichmacher enthält.
- TTS nach Ansprüchen 1 bis 5, dadurch gekennzeichent, daß die steroidhormonhaltige Matrix als Weichmacher Zitronensäuretriester enthält.
- TTS nach Ansprüchen 1 bis 6, dadurch gekennzeichnet, daß es Östrogene oder Gestagene alleine oder in Kombination derselben enthält.
- TTS nach Ansprüchen 1 bis 7, dadurch gekennzeichnet, daß es Androgene enthält.
- TTS nach Ansprüchen 1 bis 8, dadurch gekennzeichnet, daß die Trägerfolie matrixseitig eine Metalldampf- oder Oxidbeschichtung aufweist.
- Verfahren zur Herstellung eines Transdermalen Therapeutischen Systems (TTS) nach Ansprüchen 1 und 3 bis 9, dadurch gekennzeichnet, daß (1) eine homogene, beschichtungsfähige steroidhormonhaltige Matrixmasse durch Schmelzextrusion erzeugt wird, indem in einer bis zu 200°C heißen Polymerschmelze, bestehend aus einem ammoniogruppenhaltigen Methacrylatcopolymeren und mindestens einem Weichmacher alleine oder in Mischung mit einem Ethylenacrylat-Terpolymeren, wenigstens bis zu 2 Gewichtsprozent eines jeden Steroidhormons kontinuierlich eingewogen und ungeschmolzen eingearbeitet werden, (2) kontinuierlich ein Träger mit der nach (1) erzeugten heißen wirkstoffhaltigen Polymerschmelze in einer Dicke von 0,02 bis 0,4 mm beschichtet wird, (3) das gemäß (2) erhaltene 2-Schichtlaminat mit einer Deckschicht versehen wird und (4) hierauf ein größeres wirkstofffreies Pflaster zur Fixierung des TTS auf der Haut aufgebracht wird.
- Verfahren zur Herstellung eines TTS nach Ansprüchen 2 und 3 bis 9, dadurch gekennzeichnet, daß eine homogene, beschichtungsfähige steroidhormonhaltige Matrixmasse durch Schmelzextrusion gebildet wird, indem in einer bis zu 200°C heißen Polymerschmelze, bestehend aus einem ammoniogruppenhaltigen Methacrylatcopolymeren und mindestens einem Weichmacher, alleine oder in Mischung mit einem Ethylenacrylat-Terpolymeren, wenigstens bis zu 2 Gewichtsprozent eines jeden Steroidhormons kontinuierlich eingewogen und ungeschmolzen eingearbeitet werden, kontinuierlich ein geeigneter Träger mit der heißen wirkstoffhaltigen Polymerschmelze in einer Dicke von 0,02 bis 0,4 mm beschichtet wird und hierauf ein wirkstofffreier Klebefilm, bestehend aus vernetztem Acrylat-Copolymeren zur Fixierung an der Haut aufgebracht wird.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19728517A DE19728517C2 (de) | 1997-07-04 | 1997-07-04 | TTS zur Verabreichung von Sexualsteroidhormonen und Verfahren zu seiner Herstellung |
DE19728517 | 1997-07-04 | ||
PCT/EP1998/003950 WO1999001116A1 (de) | 1997-07-04 | 1998-06-29 | Transdermales therapeutisches system (tts) zur verabreichung von sexualsteroidhormonen |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1003490A1 EP1003490A1 (de) | 2000-05-31 |
EP1003490B1 true EP1003490B1 (de) | 2002-09-11 |
Family
ID=7834591
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98939550A Expired - Lifetime EP1003490B1 (de) | 1997-07-04 | 1998-06-29 | Transdermales therapeutisches system (tts) zur verabreichung von sexualsteroidhormonen |
Country Status (18)
Country | Link |
---|---|
US (1) | US6562367B1 (de) |
EP (1) | EP1003490B1 (de) |
JP (1) | JP2002508778A (de) |
KR (1) | KR100370647B1 (de) |
CN (1) | CN1195501C (de) |
AT (1) | ATE223710T1 (de) |
AU (1) | AU749474B2 (de) |
BR (1) | BR9815512A (de) |
CA (1) | CA2295720A1 (de) |
DE (2) | DE19728517C2 (de) |
DK (1) | DK1003490T3 (de) |
ES (1) | ES2181257T3 (de) |
HK (1) | HK1031693A1 (de) |
IL (1) | IL133659A (de) |
NZ (1) | NZ502352A (de) |
PT (1) | PT1003490E (de) |
WO (1) | WO1999001116A1 (de) |
ZA (1) | ZA985864B (de) |
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DE19828274C2 (de) * | 1998-06-25 | 2002-11-28 | Rottapharm Bv | Transdermales therapeutisches System, enthaltend Hormone und Kristallisationsinhibitoren |
DE19828273B4 (de) * | 1998-06-25 | 2005-02-24 | Lts Lohmann Therapie-Systeme Ag | Transdermales therapeutisches System, enthaltend Hormone und Kristallisationsinhibitoren |
AU3478200A (en) * | 1999-02-02 | 2000-08-25 | Ortho-Mcneil Pharmaceutical, Inc. | Method of manufacture for transdermal matrices |
DE10012908B4 (de) * | 2000-03-16 | 2005-03-17 | Lts Lohmann Therapie-Systeme Ag | Stabilisierte übersättigte transdermale therapeutische Matrixsysteme und Verfahren zu ihrer Herstellung |
DE10033855A1 (de) * | 2000-07-12 | 2002-01-31 | Hexal Ag | Matrixkontrolliertes transdermales System mit Sulfonsäuresalz eines ACE-Hemmers |
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Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6139868A (en) * | 1986-08-28 | 2000-10-31 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
CA2075517C (en) * | 1992-04-01 | 1997-03-11 | John Wick | Transdermal patch incorporating a polymer film incorporated with an active agent |
DE4310012A1 (de) * | 1993-03-27 | 1994-09-29 | Roehm Gmbh | Dermales therapeutisches System aus einer schmelzfähigen Poly(meth)acrylat-Mischung |
DE4332094C2 (de) * | 1993-09-22 | 1995-09-07 | Lohmann Therapie Syst Lts | Lösemittelfrei herstellbares Wirkstoffpflaster und Verfahren zu seiner Herstellung |
ES2177962T3 (es) * | 1996-03-25 | 2002-12-16 | Lohmann Therapie Syst Lts | Sistema de administracion transdermica de reducido espesor de aplicacion y elevada flexibilidad, y proceso de fabricacion del mismo. |
DE19653605C2 (de) | 1996-12-20 | 2002-11-28 | Roehm Gmbh | Haft- und Bindemittel für dermale oder transdermale Therapiesysteme und dessen Verwendung zur Herstellung eines transdermalen Therapiesystems |
-
1997
- 1997-07-04 DE DE19728517A patent/DE19728517C2/de not_active Expired - Fee Related
-
1998
- 1998-06-29 BR BR9815512-1A patent/BR9815512A/pt not_active Application Discontinuation
- 1998-06-29 JP JP50630199A patent/JP2002508778A/ja not_active Ceased
- 1998-06-29 WO PCT/EP1998/003950 patent/WO1999001116A1/de active IP Right Grant
- 1998-06-29 EP EP98939550A patent/EP1003490B1/de not_active Expired - Lifetime
- 1998-06-29 CA CA002295720A patent/CA2295720A1/en not_active Abandoned
- 1998-06-29 AT AT98939550T patent/ATE223710T1/de not_active IP Right Cessation
- 1998-06-29 DK DK98939550T patent/DK1003490T3/da active
- 1998-06-29 AU AU88021/98A patent/AU749474B2/en not_active Ceased
- 1998-06-29 US US09/462,033 patent/US6562367B1/en not_active Expired - Fee Related
- 1998-06-29 ES ES98939550T patent/ES2181257T3/es not_active Expired - Lifetime
- 1998-06-29 KR KR10-2000-7000015A patent/KR100370647B1/ko not_active IP Right Cessation
- 1998-06-29 IL IL13365998A patent/IL133659A/en not_active IP Right Cessation
- 1998-06-29 NZ NZ502352A patent/NZ502352A/en unknown
- 1998-06-29 DE DE59805536T patent/DE59805536D1/de not_active Expired - Fee Related
- 1998-06-29 CN CNB988088606A patent/CN1195501C/zh not_active Expired - Fee Related
- 1998-06-29 PT PT98939550T patent/PT1003490E/pt unknown
- 1998-07-03 ZA ZA985864A patent/ZA985864B/xx unknown
-
2001
- 2001-04-02 HK HK01102358A patent/HK1031693A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
IL133659A (en) | 2004-07-25 |
BR9815512A (pt) | 2001-11-27 |
US6562367B1 (en) | 2003-05-13 |
JP2002508778A (ja) | 2002-03-19 |
DE19728517A1 (de) | 1999-01-07 |
ATE223710T1 (de) | 2002-09-15 |
ES2181257T3 (es) | 2003-02-16 |
DE59805536D1 (de) | 2002-10-17 |
KR100370647B1 (ko) | 2003-02-05 |
DE19728517C2 (de) | 1999-11-11 |
WO1999001116A1 (de) | 1999-01-14 |
DK1003490T3 (da) | 2002-10-14 |
HK1031693A1 (en) | 2001-06-22 |
AU8802198A (en) | 1999-01-25 |
CA2295720A1 (en) | 1999-01-14 |
CN1269716A (zh) | 2000-10-11 |
CN1195501C (zh) | 2005-04-06 |
EP1003490A1 (de) | 2000-05-31 |
KR20010021493A (ko) | 2001-03-15 |
PT1003490E (pt) | 2003-01-31 |
IL133659A0 (en) | 2001-04-30 |
AU749474B2 (en) | 2002-06-27 |
ZA985864B (en) | 1998-10-23 |
NZ502352A (en) | 2001-08-31 |
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